Pharmaceutical composition having uniform drug distribution and potency

ABSTRACT

Pharmaceutical compositions having uniform drug distribution and potency utilizing laxofoxifene as an active ingredient and containing a silicon dioxide to reduce loss of the active ingredient during the manufacturing process and methods for manufacturing such compositions are disclosed.

CROSS REFERENCE TO RELATED APPLICATION

This application is a continuation of U.S. patent application Ser. No.10/612,679, filed on Jul. 1, 2003 now abandoned which claims priority ofU.S. provisional application No. 60/395,090 filed on Jul. 10, 2002.

FIELD OF THE INVENTION

The present invention relates to pharmaceutical compositions havinguniform drug distribution and potency utilizing lasofoxifene as anactive ingredient and containing a silicon dioxide to reduce loss of theactive ingredient during the manufacturing process. Methods for use inthe manufacture of such compositions are also disclosed.

BACKGROUND

U.S. Pat. No. 5,552,412 describes a class of potent and orally activeselective estrogen receptor modulators (SERMS) (e.g., derivatives oftetrahydronaphthalen-2-ol) which are useful in the treatment orprevention of breast cancer, osteoporosis, obesity, cardiovasculardisease, hypercholesterolemia, endometriosis and prostatic disease.These particular SERMS are of interest due to their improved oralbioavailability over current commercially available SERMS (e.g.raloxifene). The SERMS described in U.S. Pat. No. 5,552,412 are verypotent thus allowing for low dosage forms. However, the formulation ofcompositions at the lower dose range presents a challenge in maintainingconsistent potency and uniformity in the drug product manufacturingprocess. Of particular concern is the loss of active ingredient fromadherence to or absorption onto metal surfaces to which the active SERMis exposed during the blending step (e.g., contact with metal blenderblades and vessel surfaces). Although one can effectively implement amanual brushing step to recover active ingredient adhered to the metalsurfaces in small scale equipment, a manual brushing step is neitherefficient nor desirable in a production scale environment. Liquidprocesses can minimize the drug loss issues during drug productmanufacturing; however, compounds that are sensitive to oxidation (e.g.,tetrahydronaphthalen-2-ol derivatives) make liquid processes verydifficult to perform without degradation of the active ingredient.Therefore, there is a need for an improved formulation and process thatwould minimize adherence of active ingredients onto metal surfacesduring the manufacture of medicaments, in particular, those having a lowdosage content.

SUMMARY

The present invention provides a pharmaceutical composition having acore containing about 0.3 to about 14.0 w/w % ofcis-6-phenyl-5-[4-(2-pyrrolidin-1-ylethoxy)phenyl]-5,6,7,8-tetrahydronaphthalen-2-ol;a prodrug thereof, or a pharmaceutically acceptable salt, hydrate orsolvate of the compound or the prodrug, about 3.0 w/w % of adisintegrant, about 0.5 w/w % of a glidant, about 1.0 w/w % of alubricant and about 77.0 w/w % to about 91.0 w/w % of a diluent/filler,and an aqueous coating comprising about 1.5 w/w % of a polymer, about0.9 w/w % of an opacifier, about 0.4 w/w % of a plasticizer, about 1.5w/w % of a pharmaceutically acceptable diluent/filler and optionally acolorant.

The present invention also provides an encapsulated pharmaceuticalcomposition having as an active ingredient, about 0.3 to about 14.0 w/w%cis-6-phenyl-5-[4-(2-pyrrolidin-1-ylethoxy)phenyl]-5,6,7,8-tetrahydronaphthalen-2-ol;a prodrug thereof, or a pharmaceutically acceptable salt, hydrate orsolvate of the compound or the prodrug, about 3.0 w/w % of adisintegrant, about 0.5 w/w % of a glidant, about 1.0 w/w % of alubricant and about 81.0 w/w % to about 95.0 w/w % of a diluent/filler.

Further, the present invention provides a method for manufacturing apharmaceutical composition having uniform drug distribution and potency.The method includes (in the following order) the steps of: (1) blendingsilicon dioxide and at least one pharmaceutically acceptable excipient,carrier or diluent in a high shear granulator for an appropriate amountof time (about 5 minutes) to produce a blended mixture; (2) adding anactive ingredient to the granulator and blending for an additionalperiod of time (about 10 to about 15 minutes) to form an active blend;(3) transferring the active blend from the granulator to a blender; (4)optionally, adding one or more additional pharmaceutically acceptableexcipients, carriers or diluents to the active blend; and (5) blendingfor a suitable period of time (about 5 minutes) to form a pharmaceuticalcomposition having uniform distribution of the active ingredient anduniform potency. The resultant blended composition may then be processedfurther into a desired unit dosage form. In a preferred dosage form, theactive ingredient is present in an amount from about 0.01 to 10.0 mg perunit dose (preferably from about 0.05 to about 5.0 mg, more preferablyfrom about 0.05 to about 4.0 mg, even more preferably from about 0.1 toabout 3.5 mg, and most preferably from about 0.1 to about 2.5 mg perunit dose) and the silicon dioxide is present in an amount from about0.1 to about 2% by weight of the unit dosage form (more preferably fromabout 0.15 to about 1.0% by weight of the unit dosage form and mostpreferably from about 0.25 to about 0.75% by weight of the unit dosageform).

In another embodiment of the present invention, a pharmaceuticalcomposition is provided that is prepared using the method describedabove. In particular, a low dosage pharmaceutical composition isprovided that comprises an active ingredient (preferably lasofoxifene),a silicon dioxide, and at least one pharmaceutically acceptableexcipient, carrier, or diluent wherein the active ingredient is presentin an amount less than 4.0% w/w active ingredient (more preferably≧about 0.01% w/w active ingredient and <4% w/w active ingredient, evenmore preferably ≧about 0.01% w/w active ingredient and ≦about 3.5% w/wactive ingredient, most preferably ≧about 0.1% w/w active ingredient and≦about 2.5% w/w active ingredient) and the silicon dioxide is present inan amount from about 0.1 to about 2 weight percent.

In another embodiment of the present invention, a low dosage immediaterelease pharmaceutical composition is provided comprising a corecontaining, as an active ingredient, about 0.3 to about 0.7 w/w %cis-6-phenyl-5-[4-(2-pyrrolidin-1-ylethoxy)phenyl]-5,6,7,8-tetrahydronaphthalen-2-ol;a prodrug thereof, or a pharmaceutically acceptable salt, hydrate orsolvate of the compound or the prodrug, about 3.0 w/w % of adisintegrant, about 0.5 w/w % of a glidant, about 1.0 w/w % of alubricant and about 91.0 w/w % of a diluent/filler, and an aqueouscoating comprising about 1.5 w/w % of a polymer, about 0.9 w/w % of anopacifier, about 0.4 w/w % of a plastisizer, about 1.5 w/w % of apharmaceutically acceptable diluent/filler and optionally a colorant.

In yet another embodiment of the present invention, a medicament isprovided that is prepared by the method described above into a unitdosage form, in particular a low dosage form.

DEFINITIONS

As used herein, the term “uniform distribution” refers to a blendedmixture, which meets the FDA criteria (Guidance for Industry ANDA's:Blend Uniformity Analysis, published August 1999) of 10 individual blendsamples achieving 90-110% potency of the theoretical strength with anRSD of <5% for all blend samples.

The term “uniform potency” refers to a blended mixture that maintains adrug substance activity level greater than or equal to about 90%throughout the manufacturing process.

The phrase “pharmaceutically acceptable” indicates that the substance orcomposition must be compatible chemically and/or toxicologically, withthe other ingredients comprising a formulation, and/or the mammal beingtreated therewith.

The term “active ingredient” refers to a therapeutically activecompound, as well as any prodrugs thereof and pharmaceuticallyacceptable salts, hydrates and solvates of the compound and theprodrugs.

The term “appropriate period of time” or “suitable period of time”refers to the period of time necessary to achieve a desired effect orresult. For example, a mixture may be blended until a potencydistribution is reached that is within an acceptable qualitative rangefor a given application or use of the blended mixture.

As used herein, the term “unit dose” or “unit dosage” refers to aphysically discrete unit that contains a predetermined quantity ofactive ingredient calculated to produce a desired therapeutic effect.The unit dose or unit dosage may be in the form of a tablet, capsule,sachet, etc. referred to herein as a “unit dosage form.”

The term “immediate release” refers to pharmaceutical dosage forms thatprovide release immediately following drug administration.

The term “timed release” refers to pharmaceutical dosage forms thatprevent drug release after drug administration until a certain amount oftime has passed.

The term “sustained release” refers to pharmaceutical dosage forms thatprovide substantially continuous release over a predetermined timeperiod.

DETAILED DESCRIPTION

The present invention provides a pharmaceutical composition having acore containing about 0.3 to about 14.0 w/w % ofcis-6-phenyl-5-[4-(2-pyrrolidin-1-ylethoxy)phenyl]-5,6,7,8-tetrahydronaphthalen-2-ol;a prodrug thereof, or a pharmaceutically acceptable salt, hydrate orsolvate of the compound or the prodrug, about 3.0 w/w % of adisintegrant, about 0.5 w/w % of a glidant, about 1.0 w/w % of alubricant and about 77.0 w/w % to about 91.0 w/w % of a diluent/filler,and an aqueous coating comprising about 1.5 w/w % of a polymer, about0.9 w/w % of an opacifier, about 0.4 w/w % of a plasticizer, about 1.5w/w % of a pharmaceutically acceptable diluent/filler and optionally acolorant.

The present invention also provides an encapsulated pharmaceuticalcomposition having as an active ingredient, about 0.3 to about 14.0 w/w%cis-6-phenyl-5-[4-(2-pyrrolidin-1-ylethoxy)phenyl]-5,6,7,8-tetrahydronaphthalen-2-ol;a prodrug thereof, or a pharmaceutically acceptable salt, hydrate orsolvate of the compound or the prodrug, about 3.0 w/w % of adisintegrant, about 0.5 w/w % of a glidant, about 1.0 w/w % of alubricant and about 81.0 w/w % to about 95.0 w/w % of a diluent/filler.

Further, the present invention provides a process for maintaininguniformity and potency during the manufacture of a pharmaceuticalcomposition containing a highly potent active ingredient. The processincludes a means for reducing the loss of active ingredients that adhereto the metal surfaces of equipment during the manufacturing process of apharmaceutical composition or medicament. Active ingredients ofparticular interest are SERM compounds of Formula (I) below:

where E and B are independently selected from CH and N; R¹ is hydrogen,hydroxy, fluoro or chloro; and G is

a prodrug thereof, or a pharmaceutically acceptable salt, hydrate orsolvate of the compound or the prodrug.

Preferred compounds includecis-6-(4-fluoro-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalen-2-ol;(−)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalen-2-ol;cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalen-2-ol;cis-1-[6′-pyrrolodinoethoxy-3′-pyridyl]-2-phenyl-6-hydroxy-1,2,3,4-tetrahydrohaphthalen-1-(4′-pyrrolidinoethoxyphenyl)-2-(4″-fluorophenyl)-6-hydroxy-1,2,3,4-tetrahydroisoquinoline;cis-6-(4-hydroxyphenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalen-2-ol;and1-(4′-pyrrolidinolethoxyphenyl)-2-phenyl-6-hydroxy-1,2,3,4-tetrahydroisoquinoline.A more preferred compound iscis-6-phenyl-5-[4-(2-pyrrolidin-1-ylethoxy)phenyl]-5,6,7,8-tetrahydronaphthalen-2-ol;a prodrug thereof, or a pharmaceutically acceptable salt, hydrate orsolvate of the compound or the prodrug.

The compounds of Formula (I) are very potent compounds thus requiringspecial handling to reduce operator exposure during the manufacturingprocess. In addition, the compounds of Formula (I) may be sensitive tooxidation, which may limit or preclude the use of liquids and materialscontaining peroxide contaminants (e.g., polyethylene glycols) duringdrug product manufacture. Conventional methods for manufacturing tabletstypically use a wet or dry granulation step prior to compression into atablet.

The types of mixing processes for a dry granulation can be divided intotwo broad categories: (i) batch, and (ii) continuous. The most prevalenttype used in the pharmaceutical industry is the batch type, which mixesa sub-lot or total lot of a formulation at one time. In a batch-typemixer, particle movement is achieved by rotation of the entire mixershell or body. For schematics and a description of the different typesof batch-type mixers, see Pharmaceutical Dosage Forms, Vol. 2,Lieberman, H. A., L. Lachman, and J. B. Schwartz (Eds.), Marcel Dekker,Inc., New York, pp 40-57 (1990).

In a Blend/Mill/Blend dry granulation process, the following steps aregenerally employed:

-   (1) pass an active ingredient through an appropriately sized sieve    and then blend in a blender (e.g., twin shell blender) for an    appropriate period of time to produce a blended mixture;-   (2) filter an excipient blend through an appropriately sized sieve    and add a portion of the filtered excipient blend to the blender    containing the active ingredient;-   (3) blend the mixture for an appropriate period of time;-   (4) filter the active blend through an appropriately sized screen;-   (5) charge a blender with half of the remaining filtered excipient    blend followed by the filtered active blend from step (4);-   (6) blend the mixture for an appropriate period of time;-   (7) add the remaining filtered excipient blend to the active mixture    and blend for an appropriate period of time;-   (8) pass the blended mixture from step (7) through a mill;-   (9) blend the active mixture from step (8) for an appropriate period    of time in a blender; and-   (10) add any additional excipients, carriers or diluents and blend    until an acceptable distribution of materials is achieved.

The conventional blend/mill/blend dry process presents severaldisadvantages. For example, it is labor intensive, the dusty operationincreases the operator's exposure to the active ingredient, and theincreased exposure to metal surfaces increases the risk of potency loss.In addition, segregation problems are observed with mixtures having wideparticle size distribution and large differences in particle densities.Tumbling-type blenders are generally not suitable for fine particulatesystems because there may not be enough shear to reduce particleagglomeration and, if the powders are free flowing, serial dilution maybe required for the addition of low dose active ingredients.

When the dry granulation process described above was used to blend aformulation containing a compound of Formula (I), a non-uniformdistribution of potency was observed across the granulation particles.Although the potential for operator exposure to the active ingredient isgreatly reduced in a conventional wet granulation process, the activeingredient is exposed to liquids and dissolved oxygen during theprocess, which increases the potential for oxidation of the compound.Attempts to reduce the chemical instability of the compound of Formula(I) in a wet granulation process have not been successful. However,Applicant discovered that the use of high shear wet process blendingequipment adapted for use as a dry process addressed both the operatorexposure to the drug and reduced degradation of the active ingredientdue to oxidation observed during the conventional dry and wetgranulation processes.

High-speed granulators are stationary shell mixers with a largemixer-scraper blade that mixes the ingredients, eliminates dead spots inthe mixer container and presents the mixer contents to a high-speedchopper blade, which intimately mixes the ingredients. The equipment isextremely rapid and provides intimate solids/solids mixing. In avertical type of mixer (e.g., equipment available from LÖDIGEIndustries, Paderborn, Germany; NIRO Inc., Columbia, Md.; and DIOSNADierks & Soehne GmbH, Osnabrueck, Germany), rotating mixing impellersmix the particles centrifugally at high speed causing a highly fluidizedvortex of material. A chopper, rotating at a very high speed, interruptsthe ascending circulation of the material and diverts the product into avertical flow. For a more detailed description, see Record, P. C.,Manuf. Chem. Aerosol. News, 50, 65 (1979). Other suitable high-speedgranulators include Spectrum™ and Pharma Matrix™ (both available fromNiro Pharma Systems, Columbia, Md.).

The present invention provides a dry process that comprises thefollowing steps:

-   (1) blending at least one pharmaceutically acceptable excipient,    carrier or diluent in a high shear granulator for an appropriate    amount of time;-   (2) adding an active ingredient to the granulator and blending for    an additional period of time to form an active blend;-   (3) transferring the active blend from the granulator to a blender;-   (4) optionally, adding one or more additional pharmaceutically    acceptable excipients, carriers or diluents to the mixture; and-   (5) blending for a suitable period of time to form a final    pharmaceutical composition having a uniform distribution of the    active ingredient in the composition.

The final pharmaceutical composition is processed into a unit dosageform (e.g., tablet, capsule or sachet) and then packaged fordistribution. The processing step will vary depending upon theparticular unit dosage form. For example, a tablet is generallycompressed under pressure into a desired shape and a capsule or sachetemploys a simple fill operation. Those skilled in the art are well awareof the procedures used for manufacturing the various unit dosage forms.

The active blend generally includes one or more pharmaceuticallyacceptable excipients, carriers or diluents. The particular carrier,diluent or excipient used will depend upon the means and purpose forwhich the active ingredient is being applied. In general, a tabletformulation includes materials such as diluents, binders, lubricants,disintegrants and mixtures thereof. Suitable diluents include varioustypes of starch, lactose, mannitol, kaolin, calcium phosphate orsulfate, inorganic salts (e.g., sodium chloride), powdered sugar, andpowdered cellulose derivatives. More specifically, examples of diluentsor fillers include lactose, mannitol, xylitol, dextrose, sucrose,sorbitol, compressible sugar, microcrystalline cellulose, powderedcellulose, starch, pregelatinized starch, dextrates, dextran, dextrin,dextrose, maltodextrin, calcium carbonate, dibasic calcium phosphate,tribasic calcium phosphate, calcium sulfate, magnesium carbonate,magnesium oxide, poloxamers such as polyethylene oxide and hydroxypropylmethyl cellulose. To ensure content uniformity of the blend, a volumemean diameter drug substance particle size of less than or equal toabout 30 microns is preferably utilized. Preferred diluents aremicrocrystalline cellulose (e.g., Avicel® PH102 or PH101 available fromFMC Pharmaceutical, Philadelphia, Pa.) and lactose. The mean particlesize for the microcrystalline cellulose generally ranges from about 90μm to about 200 μm. Suitable grades of lactose include anhydrous lactose(about 152 μm mean), lactose monohydrate and spray dried lactose (e.g.,Fast Flo™ lactose, about 87 μm mean, available from Foremost Corp.,Baraboo, Wis.). Generally, the microcrystalline cellulose is present inan amount from about 20 wt % to about 90 wt % and the lactose is presentin an amount from about 65 wt % to about 85 wt %.

If desired, a binder may be added. Suitable binders include substancessuch as celluloses (e.g., cellulose, methylcellulose, ethylcellulose,and hydroxymethylcellulose), polypropylpyrrolidone, polyvinylprrolidone,gelatin, gum arabic, polyethylene glycol, starch, sugars (e.g., lactose,sucrose, fructose, and glucose), natural and synthetic gums (e.g.,acacia, alginates, and gum arabic) and waxes.

A lubricant is typically used in a tablet formulation to prevent thetablet and punches from sticking in the die. Suitable lubricants includecalcium stearate, glyceryl monostearate, glyceryl palmitostearate,hydrogenated vegetable oil, light mineral oil, magnesium stearate,mineral oil, polyethylene glycol, sodium benzoate, sodium laurylsulfate, sodium stearyl fumarate, stearic acid, talc and zinc stearate.A preferred lubricant is magnesium stearate. The magnesium stearate isgenerally present in an amount from about 0.25 wt % to about 5.0% wt %.

Disintegrants may also be added to the composition to break up thedosage form and release the compound. Suitable disintegrants includesodium starch glycolate, sodium carboxymethyl cellulose, calciumcarboxymethyl cellulose, croscarmellose sodium, polyvinylpyrrolidone,methyl cellulose, microcrystalline cellulose, powdered cellulose, loweralkyl-substituted hydroxypropyl cellulose, polacrilin potassium, starch,pregelatinized starch and sodium alginate. Of these, croscarmellosesodium, lower alkyl-substituted hydroxypropyl cellulose, methylcellulose and polacrilin potassium are preferred, with croscarmellosesodium being most preferred. The croscarmellose sodium is generallypresent in an amount from about 0.5 wt % to about 5.0 wt %. The amountof disintegrant included in the dosage form will depend on severalfactors, including the properties of the dispersion, the properties ofthe porosigen (discussed below), and the properties of the disintegrantselected. Generally, the disintegrant will comprise from 1 wt % to 25 wt%, preferably from 3 wt % to 20 wt % of the dosage form.

The aqueous coating of the present invention comprises a polymer, anopacifier, a plastisizer, a pharmaceutically acceptable diluent/fillerand optionally a colorant.

Examples of polymers include cellulosics such as hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose,methylhydroxyethylcellulose, methylcellulose, and sodiumcarboxymethylcellulose. Further examples of polymers include vinyls suchas polyvinyl pyrrolidone. Of these polymers, the most preferred ishydroxypropyl methylcellulose.

Examples of opacifiers include titanium dioxide and talc.

Examples of plasticizers include polyhydric alcohols such as glyceroland polyethylene glycols and acetate esters such as glyceryl triacetate(triacetin) and triethyl citrate.

Examples of glidants include silicon dioxide, talc and cornstarch.

Optionally, the compositions of the present invention may include acolorant. Such colorants are available from a number of commercialvendors and are well known to those skilled in the art.

Other useful additives include materials such as agents for retardingdissolution (e.g., paraffin), resorption accelerators (e.g., quaternaryammonium compounds), surface active agents (e.g., cetyl alcohol,glycerol monostearate, and sodium lauryl sulfate), adsorptive carriers(e.g., kaolin and bentonite), preservatives, sweeteners, coloringagents, flavoring agents (e.g., citric acid, menthol, glycine or orangepowder), stabilizers (e.g., citric acid or sodium citrate), binders(e.g., hydroxypropylmethylcellulose), and mixtures thereof.

There is a great deal of flexibility in the order of addition ofcomponents into the high shear granulator for the initial blending step.Preferably, the drug substance is not added to the high shear bowlfirst. The typical blending time for the blending in the high sheargranulator is from about 10 minutes to about 15 minutes. Althoughblending times greater than 15 minutes can be used, care should be takennot to demix the blend. The granulator impeller speed is typically runat about 55% to about 65% unit capacity and the chopper is preferablyrun at the slowest speed setting. Excessive impeller speeds could leadto fluidization of the blend and produce a blend potency loss.

After the high shear blending step, the active blend is blended in atwin shell “V” or bin blender. The typical blending time is about 5minutes, although small-scale lots have been successfully blended up toabout 15 minutes. The lubricant is then added to the active blend andblended for about 5 minutes in the twin shell “V” or bin blender.

The process described above provides efficient mixing and a more uniformdistribution of the active ingredient without significant degradation ofthe active ingredient; however, the loss of active ingredient due toadherence or attraction of the compound to the metal surfaces of theequipment (e.g., blades and vessel surfaces) presented an additionalchallenge especially for low dosage formulations (e.g., less than 4 mgper unit dose). The addition of a glidant such as talc did not resolvethe problem. Although the addition of talc to the formulation reducedthe loss of active ingredient in the blending process (potency increasefrom 77.2% to 91.0% of the blended composition), talc did not completelyprevent adhesion to the metal surface. When a manual brushing step wasimplemented after blending the talc formulation, an increase in potencyto 96.8% was observed which indicates that about 5% to about 6% of theactive ingredient is still adhering to the metal surface. A 5-6% loss ofa very potent active ingredient, such as the compounds of Formula (I),is significant. However, when silicon dioxide (e.g., Syloid™ 244FPavailable from W.R. Grace, Columbia, Md.) was added to the formulation,an increase of potency from 77.2% to 96.3% of the blended compositionwas observed without the addition of a manual brushing step.

Although the addition of silicon dioxide to pharmaceutical formulationshave been utilized to improve the flow of powder blends and minimizetablet weight variation, the incorporation of SiO₂ (as observed above)unexpectedly and surprisingly reduced the loss of active ingredient dueto absorption or adherence to the metal surfaces of the processequipment. A variety of silicon dioxides are available from a number ofcommercial vendors and are well known to those skilled in the art. Aparticularly useful silicon dioxide is colloidal silicon dioxide whichis a submicron fumed silica prepared by the vapor-phase hydrolysis of asilicon compound, such as silicon tetrachloride. Colloidal silica is anamorphous powder, which is available commercially from a number ofsources, including Cabot Corporation, Boston, Mass. (Cab-O-Sil™);Degussa, Inc., Düsseldorf, Germany (Aerosil™); E.I. DuPont & Co.,Wilmington, Del.; and W.R. Grace & Co., Columbia, Md. (Syloid™).Colloidal silicon dioxide is also known as colloidal silica, fumedsilica, light anhydrous silicic acid, silicic anhydride, and silicondioxide fumed, among others. A variety of commercial grades of colloidalsilicon dioxide are produced by varying the manufacturing process. Thesemodifications do not affect the silica content, specific gravity,refractive index, color or amorphous form. However, these modificationsare known to change the particle size, surface areas, and bulk densitiesof the colloidal silicon dioxide products. The mean particle size forthe silicon dioxide is generally less than or equal to about 15 μm/bulkdensity (less than or equal to about 21.0 lbs./ft³ (336 kg/m³)).Preferably, the silicon dioxide is in the form of a dry powder and not aliquid suspension.

The silicon dioxide is generally present in an amount from about 0.1 toabout 2% by weight of the dosage form, preferably, in an amount fromabout 0.15 to about 1.0% by weight and most preferably in an amount fromabout 0.10 to about 0.50% by weight of the dosage form.

Procedures for making compounds of Formula (I) are described in U.S.Pat. No. 5,552,412, incorporated herein by reference, and the resolutionof racemic mixtures is described in WO97/16434. The active ingredientmay be used per se or in the form of its pharmaceutically acceptablesalt, solvate and/or hydrate. The term “pharmaceutically acceptablesalt” refers to non-toxic acid addition salts derived from inorganic andorganic acids. Suitable salt derivatives include halides, thiocyanates,sulfates, bisulfates, sulfites, bisulfites, arylsulfonates,alkylsulfates, phosphonates, monohydrogen-phosphates,dihydrogenphosphates, metaphosphates, pyrophosphonates, alkanoates,cycloalkylalkanoates, arylalkonates, adipates, alginates, aspartates,benzoates, fumarates, glucoheptanoates, glycerophosphates, lactates,maleates, nicotinates, oxalates, palmitates, pectinates, picrates,pivalates, succinates, tartarates, citrates, camphorates,camphorsulfonates, digluconates, trifluoroacetates, and the like. Apreferred salt of compounds of Formula (I) is tartrate (in particular,D-tartrate) or citrate. A preferred compound is lasofoxifene(cis-6-phenyl-5-[4-(2-pyrrolidin-1-ylethoxy)phenyl]-5,6,7,8-tetrahydronaphthalen-2-ol).The active ingredient is generally present in a pharmaceuticalcomposition in an amount less than or equal to about 14% w/w. For a lowdosage application, the active ingredient is typically present in thepharmaceutical composition in an amount less than 4.0% w/w activeingredient, more preferably ≧about 0.01% w/w active ingredient and <4%w/w active ingredient, even more preferably ≧about 0.01% w/w activeingredient and ≦about 3.5% w/w active ingredient, most preferably ≧about0.1% w/w active ingredient and ≦about 2.5% w/w active ingredient).

The pharmaceutical composition can be used to produce unit dosage formscontaining about 0.05 mg to about 10.0 mg active ingredient per unitdosage, preferably, about 0.1 mg to about 5.0 mg active ingredient perunit dosage. The tablet size (i.e., unit dosage form) is typicallybetween about 100 mg and 600 mg. As used herein, “low dosage form”refers to a unit dose containing less than about 5.0 mg activeingredient. A typical low dosage form contains between about 0.01 andabout 5.0 mg active ingredient, preferably between about 0.05 mg andabout 4.0 mg, more preferably between about 0.1 mg and about 3.5 mg,most preferably between about 0.1 mg and 2.5 mg.

For example, the tablet formulation for a 0.25 mg, 0.1 mg and 0.05 mgtablet typically consists of a blend containing about 0.14% w/w activeingredient and the tablet size is varied to achieve the proper dosage;whereas, a 0.5 mg tablet formulation generally contains a blend havingabout 0.68% w/w active ingredient. The concentration of activeingredient in the final pharmaceutical composition is generally adjustedby increasing or decreasing the amount of diluent (e.g., lactose) addedto the formulation.

The tablets are generally prepared by compression in a rotary press.However, the particular method used for tablet formation is non-limitingand is well known to those skilled in the art. After formation of thetablets, the tablets are often coated with one or more coatings. Thetablet may be coated with a coating to mask flavor, to act as a sealantand/or to act as a receptor for printing a logo or trademark on thetablet surface. A common coating is a sugar coating (e.g., sucrose orsorbitol coating). Alternatively, the tablet may be coated with afilm-forming protecting agent(s) to modify the dissolution properties ofthe tablet. For example, the tablet may be coated with a film-formingcoating that resists dissolution for a predictable period of time thusresulting in a delayed or prolonged release of the active ingredient.Suitable film-forming protecting agents include celluloses (e.g.,hydroxypropyl-methylcellulose, hydroxypropyl cellulose,methylcellulose), polyvinyl pyrrolidone, and ethyl acrylate-methylmethacrylate copolymers. The coating formulations may also includeadditives such as solubilizing agents (e.g., triacetin), preservatives,sweeteners, flavoring agents, coloring agents and other known additivesto provide an elegant presentation of the drug. The compounds may alsobe formulated as chewable tablets, by using large amounts ofpleasant-tasting substances such as mannitol in the formulation.

Preferably, the aqueous coating of the present invention comprisesOpadry II® (Y-30-13579-A) and Opadry Clear® (YS-2-19114-A) manufacturedby Colorcon, West Point, Pa. Opadry II®, useful as an opacifying coat,contains lactose monohydrate, hydroxypropyl methyl cellulose, titaniumdioxide, triacetin and FD&C Yellow No. 6 aluminum lake. Opadry Clear®,useful as a polish coat, contains hydroxypropyl methylcellulose andtriacetin.

Alternatively, the active pharmaceutical blend may be filled into hardshell capsules, also referred to as the dry-filled capsule (DFC). Thecapsule formulation and manufacturing process is similar to the reportedtablet core formulation and manufacturing process. A hard shell capsulecould consist of gelatin and water or hydroxypropyl methylcellulose,water and a gelling agent (gelan gum or carageenan).

Such capsule compositions do not utilize an aqueous coating. Theencapsulated pharmaceutical composition comprises about 0.3 to about14.0 w/w % of lasofoxifene, a prodrug thereof or a pharmaceuticallyacceptable salt, hydrate or solvate of the compound or the prodrug,about 3.0 w/w % of a disintegrant, about 0.5 w/w % of a glidant, about1.0 w/w % of a lubricant and about 81.0 w/w % to about 95.0 w/w % of adiluent/filler.

The pharmaceutical composition (or formulation) may be packaged in avariety of ways. Generally, an article for distribution includes acontainer that contains the pharmaceutical composition in an appropriateform. Suitable containers are well known to those skilled in the art andinclude materials such as bottles (plastic and glass), sachets, foilblister packs, and the like. The container may also include a tamperproof assemblage to prevent indiscreet access to the contents of thepackage. In addition, the container typically has deposited thereon alabel that describes the contents of the container and any appropriatewarnings or instructions.

The pharmaceutical compositions containing the compounds of Formula (I)described herein are useful in the treatment or prevention of inter aliabreast cancer, osteoporosis, obesity, cardiovascular disease,hypercholesterolemia, endometriosis and prostatic disease. Accordingly,the pharmaceutical formulations and processes described hereincontaining the compounds of Formula (I) may be used in the manufactureof a medicament for the therapeutic applications described above.

A therapeutically effective amount of the manufactured medicament may beadministered to a human in need of such treatment or prevention. As usedherein, the term “therapeutically effective amount” refers to an amountof active ingredient which is capable of inhibiting or preventing thevarious pathological conditions or symptoms thereof and sequelae,referred to above. The terms “inhibit” or “inhibiting” refers toprohibiting, treating, alleviating, ameliorating, halting, restraining,slowing or reversing the progression, or reducing the severity of apathological condition or symptom related to or resultant from therespective condition being treated. As such, the pharmaceuticalformulations may be used for both medical therapeutic (acute or chronic)and/or prophylactic (prevention) administration as appropriate. Thedose, frequency and duration will vary depending on such factors as thenature and severity of the condition being treated, the age and generalhealth of the host and the tolerance of the host to the activeingredient. The pharmaceutical composition or medicament may be given ina single daily dose, in multiple doses during the day or even in aweekly dose. The regimen may last from about 2-3 days to several weeksor longer. Typically, the composition is administered to a human patientonce a day with a unit dosage of about 0.25 mg to about 10.0 mg, but theabove dosage may be properly varied depending on the age, body weightand medical condition of the patient and the type of administration.

The following Examples illustrate the preparation of compounds ofFormula (I) and their use in pharmaceutical compositions andmanufacturing processes of the present invention. Although a particularSERM compound (lasofoxifene) is used to illustrate the invention, itwill be understood by those skilled in the art that the inventiveprocess can be used for any compound that would benefit from increaseduniformity of potency and distribution of the active ingredient in apharmaceutical composition by means of the present invention. Theexamples are not intended to be limiting to the scope of the inventionin any respect, and should not be so construed.

EXAMPLES Preparation ofcis-6-phenyl-5-[4-(2-pyrrolidin-1-ylethoxy)phenyl]5,6,7,8-tetrahydronaphthalen-2-ol(“lasofoxifene”)

Lasofoxifene was prepared as described in U.S. Pat. No. 5,552,412 andreproduced below.

A solution of 1-[2-[4-(6-methoxy-2-phenyl-3,4dihydronaphthalen-1-yl)phenoxy]ethyl]pyrrolidine hydrochloride(nafoxidene hydrochloride) (1.0 g, 2.16 mmol) in 20 mL of absoluteethanol containing 1.0 g of palladium hydroxide on carbon washydrogenated at 60 psi (0.41 MPa) at 20° C. for 19 hr. Filtration andevaporation provided 863 mg (93%) of cis-1-{2-[4-(6-methoxy-2-phenyl1,2,3,4-tetrahydronapahthalen-1-yl)phenoxy]ethyl}pyrrolidine.

¹H-NMR (CDCl₃): δ 3.50-3.80 (m, 3H), 3.85 (s, 3H), 4.20-4.40 (m, 3H),6.80-7.00 (m, 3H); MS 428 (P⁺¹).

To a solution of 400 mg (0.94 mmol) of cis-1-{2-[4-(6-methoxy-2-phenyl1,2,3,4-tetrahydronaphthalen-1-yl)phenoxy]ethyl}pyrrolidine in 25 mL ofmethylene chloride at 0° C. was added, dropwise with stirring, 4.7 ml(4.7 mmol) of a 1.0 M solution of boron tribromide in methylenechloride. After 3 hours at room temperature, the reaction was pouredinto 100 mL of rapidly stirring saturated aqueous sodium bicarbonate.The organic layer was separated, dried over sodium sulfate, filtered,and concentrated to afford 287 mg (74% yield) of lasofoxifene as thefree base.

¹H-NMR (CDCl₃): δ 3.35 (dd, 1H), 4.00 (t, 2H), 4.21 (d, 1H), 6.35 (ABq,4H). The corresponding hydrochloride salt was prepared by treating asolution of the base with excess 4N HCl in dioxane, followed byevaporation to dryness and ether trituration (MS: 415 [P⁺¹]).

Alternatively, lasofoxifene may be prepared using the proceduresdescribed below.

Preparation of1-[2-[4-(6-methoxy-3,4-dihydronaphthalen-1-yl)phenoxy]ethyl]pyrrolidine:A mixture of anhydrous CeCl₃ (138 g, 560 mmol) and THF (500 mL) wasvigorously stirred for 2 h. In a separate flask, a solution of1-[2-(4-bromophenoxy)ethyl]pyrrolidine (100 g, 370 mmol) in THF (1000mL) was cooled to −78° C. and n-BuU (2.6 M in hexanes, 169 mL, 440 mmol)was slowly added over 20 min. After 15 min, the solution was added tothe CeCl₃ slurry cooled at −78° C. via cannula and the reaction wasstirred for 2 h at −78° C. A solution of 6-methoxy-1-tetralone (65.2 g,370 mmol) in THF (1000 mL) at −78° C. was added to the arylceriumreagent via cannula. The reaction was allowed to warm slowly to roomtemperature and was stirred for a total of 16 h. The mixture wasfiltered through a pad of Celite™. The filtrate was concentrated invacuo and 3 N HCl (500 mL) and Et₂O (500 mL) were added. After stirringfor 15 min, the layers were separated. The aqueous layer was furtherwashed with Et₂O (2×). The combined organic layers were dried (MgSO₄),filtered, and concentrated to provide 6-methoxy-1-tetralone (22 g). Theaqueous layer was basified to pH 12 with 5 N NaOH and 15% aqueous(NH₄)₂CO₃ (1000 mL) was added. The aqueous mixture was extracted withCH₂Cl₂ (2×). The organic solution was dried (MgSO₄), filtered, andconcentrated to provide a brown oil. Impurities were distilled off(110°-140° C. @0.2 mmHg) to yield the product (74 g, 57%).

¹H NMR (250 MHz, CDCl₃): δ 7.27 (d, J=8.7 Hz, 2H), 6.92-6.99 (m, 3H),6.78 (d, J=2.6 Hz, 1H), 6.65 (dd, J=8.6, 2.6 Hz, 1H), 5.92 (t, J=4.7 Hz,1H), 4.15 (t Hz, 2H), 3.80 (s, 3H), 2.94 (t, J=6.0 Hz, 2H), 2.81 (t,J=7.6 Hz, 2H), 2.66 (m, 2H), 2.37 (m, 2H), 1.84 (m, 4H).

Preparation of1-[2-[4,(2-bromo-6-methoxy-3,4-dihydronaphthalen-1-yl)phenoxy]ethyl]pyrrolidine:Pyridinium bromide perbromide (21.22 g, 60.55 mmol) was addedportionwise to a solution of1-{2-[4-(6-methoxy-3,4-dihydronaphthalen-1-yl)phenoxy]ethyl]pyrrolidine(23 g, 72 mmol) in THF (700 mL). The reaction was stirred for 60 h. Theprecipitate was filtered through a Celite pad with the aid of THF. Theoff-white solid was dissolved in CH₂Cl₂ and MeOH and was filtered awayfrom the Celite. The organic solution was washed with 0.5 N aq HClfollowed by saturated NaHCO₃ (aq). The organic solution was dried(MgSO₄), filtered, and concentrated to provide a brown solid (21.5 g,83%).

¹H NMR (250 MHz, CDCl₃): δ 7.14 (d, J=8.7 Hz, 2H), 6.97 (d, J=8.8 Hz,2H), 6.71 (d, J=2.2 Hz, 1H), 6.55 (m, 2H), 4.17 (t, J=6.0 Hz, 2H), 3.77(s, 3H), 2.96 m, (4H), 2.66 (m, 4H), 1.85 (m, 4H).

Preparation of1-{2-[4-(6-methoxy-2-phenyl-3,4-dihydronaphthalen-1yl)phenoxy]ethyl]pyrrolidinehydrochloride (Nafoxidene hydrochloride): To a mixture of 1[2-[4-(2-bromo-6-methoxy-3,4-dihydronaphthalen-1-yl)phenoxy]ethyl}pyrrolidine(19 g, 44 mmol), phenylboronic acid (7.0 g, 57 mmol), andtetrakis(triphenylphosphonium) palladium (1.75 g, 1.51 mmol) in THF (300mL) was added Na₂CO₃ (13 g, 123 mmol) in H₂O (100 mL). The reaction washeated at reflux for 18 h. The layers were separated and the organiclayer was washed with H₂O followed by brine. The organic solution wasdried (MgSO₄), filtered, and concentrated to yield 17.96 g of a brownsolid. The residue was dissolved in a 1:1 mixture of CH₂Cl₂ and EtOAc(250 mL) and 1 N HCl in Et₂O (100 mL) was added. After stirring for 2 h,product was allowed to crystallize from solution and 11 g of materialwas collected by filtration. Concentration of the mother liquor to halfits volume provided an additional 7.3 g of product.

Preparation ofcis-1-[2-[4-(6-methoxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1yl)phenoxy]ethyl]pyrrolidine:1-[2-[4-(6-Methoxy-2-phenyl-3,4-dihydronaphthalen1yl)phenoxy]ethyl]pyrrolidine hydrochloride (nafoxidene hydrochloride)(75 g, 162 mmol) was dissolved in 1000 mL of EtOH and 300 mL of MeOH.Dry Pd(OH)₂ on carbon was added and the mixture was hydrogenated on aParr shaker at 50° C. and 50 psi (0.34 MPa) for 68 h. The catalyst wasfiltered off with the aid of Celite and the solvents were removed invacuo. The resulting white solid was dissolved in CH₂Cl₂ and thesolution was washed with saturated NaHCO₃ (aq). The organic solution wasdried (MgSO₄), filtered, and concentrated to yield an off-white solid(62.6 g, 90%).

Preparation ofcis-6-phenyl-5-[4-(2-pyrrolidin-1-ylethoxy)phenyl]-5,6,7,8-tetrahydronaphthalene-2-ol:A mixture of cis-1-[2-[4-(6-methoxy-2-phenyl-1,2,3,4tetrahydronaphthalen-1-yl)phenoxy]ethyl}pyrrolidine (12 g, 28 mmol),acetic acid (75 mL), and 48% HBr (75 mL) was heated at 100° C. for 15 h.The solution was cooled and the resulting white precipitate wascollected by filtration. The hydrobromide salt (9.6 g, 69%) wasdissolved in CHCl₃/MeOH and was stirred with saturated NaHCO₃ (aq). Thelayers were separated and the aqueous layer was further extracted withCHCl₃/MeOH. The combined organic layers were dried (MgSO₄), filtered,and concentrated to yield product as an off-white foam.

¹H NMR (250 MHz, CDCl₃): δ 7.04 (m, 3H), 6.74 (m, 2H), 6.63 (d, J=8.3Hz, 2H), 6.50 (m, 3H), 6.28 (d, J=8.6 Hz, 2H), 4.14 (d, J=4.9 Hz, 1H),3.94 (t, J=5.3 Hz, 2H), 3.24 (dd, J=12.5, 4.1 Hz, 1H), 2.95 (m, 4H),4H), 2.14 (m, 1H), 1.88 (m, 4H), 1.68 (m, 1H).

The following example compares a conventional wet granulation processand a solution wet granulation process with the present invention (drygranulation process).

Example 1

The following materials used in Example 1 may be obtained from thecorresponding sources listed below:

Avicel ™ PH101 FMC Pharmaceutical (Philadelphia, PA) (microcrystallinecellulose) Lactose Fast Flo ™ 316 Foremost Corp. (Baraboo, WI) magnesiumstearate Mallinckrodt (St. Louis, MO) hydroxypropyl cellulose HerculesInc. (Hopewell, VA) sodium croscarmellose FMC Pharmaceutical(Philadelphia, PA) β-cyclodextrin sulfobutyl ether Prepared using themethod described in U.S. Pat. No. 6,153,746 silicon dioxide GraceDavison (Columbia, MD) ProSolv ™ 50 Penwest, Patterson, NJ (silicifiedmicrocrystalline cellulose)

Lasofoxifene Conventional Wet Granulation Process (Comparative Process)

The following ingredients were added to a high shear blender in thelisted order.

lactose 5.000 g microcrystalline cellulose 17.432 g  sodiumcroscarmellose 1.000 g hydroxypropyl cellulose 1.250 g silicon dioxide0.125 g Lasofoxifene 0.068 gThe mixture was blended for approximately 15 minutes. While blending, anappropriate amount of water (approximately 63% w/w of dry blend) wasadded over a 8.5 minute period and then allowed to continue blending foran additional 30 seconds to achieve the desired wet mass. The wet masswas then dried to a moisture level less than about 2% under vacuum(about 50 millibar (mB)). The dried granulation was milled through aconical mill fitted with a 0.04 inch (0.10 cm) screen and round edgeimpeller set at 1750 rpm speed. The mixture was blended for about 10minutes in a 150 cc glass bottle on a Turbula mixer. Magnesium stearate(0.125 g) was added to the mixture and then blended for about 5 minutes.The active blend was then compressed into tablets using a Kilian™ T100tablet press (available from Kilian & Co., Inc., Horsham, Pa.).

Lasofoxifene Drug in Solution Wet Granulation Process (ComparativeProcess)

Water (100 mL) was added to a 250 mL glass beaker equipped with a mixer.While stirring, β-cyclodextrin sulfobutyl ether (0.452 g) was addedfollowed by the lasofoxifene (0.113 g) and allowed to stir until theβ-cyclodextrin sulfobutyl ether and lasofoxifene dissolved and asolution was formed. The following ingredients were then added in theorder listed into a high shear blender.

lactose 5.000 g silicified microcrystalline cellulose 17.540 g  sodiumcroscarmellose 1.000 g hydroxypropyl cellulose 1.250 gThe mixture was blended for about 2 minutes. While blending, thelasofoxifene:water solution was added over a 3 minute period. The wetmass was then dried to a moisture level of less than about 1% in a 50°C. forced hot air oven. The dried granulation was passed through aconical mill fitted with a 0.055 inch (0.14 cm) screen and round edgeimpeller set at 1750 rpm speed. Magnesium stearate (0.125 g) was addedto the mixture and then blended for about 5 minutes. The active blendwas then compressed into tablets using a Manesty™ F-Press tablet press(available from Thomas Engineering Inc., Hoffman Estates, Ill.).

Lasofoxifene Dry Granulation Process

The following ingredients were added in the order listed into a highshear blender

lactose 1052.25 g   microcrystalline cellulose 375.00 g  croscarmellosesodium 45.00 g  silicon dioxide 7.50 g Lasofoxifene 5.25 gThe lactose, microcrystalline cellulose, croscarmellose sodium andsilicon dioxide were blended for 5 minutes. The lasofoxifene was addednext and blended for about 15 minutes. The active blend was thendischarged from the high shear blender and blended for about 5 minutesin a twin shell “V” blender. Magnesium stearate (7.50 g) was added tothe active blend and blended for about 5 minutes. The active blend wasroller compacted on a Vector Freund™ roller compactor unit and milledthrough a rotating granulator fitted with a 0.033″ (0.084 cm) screen(both available from Vector Corp., Marion, Iowa). The active granulationwas blended for about 5 minutes in a twin shell “V” blender. Anotherportion of magnesium stearate (7.50 g) was added to the granulation andblended for about 5 minutes. The final blend was compressed into tabletson a Kilian™ T100 rotary press.

The components of the lasofoxifene formulation were selected based onin-vivo and manufacturing performance and chemical stability. The drugsubstance has been shown to be susceptible to oxidation due to thepresence of free radicals or the presence of metal impurities, whichcould indirectly lead to free radical formation through chelation. Thedisintegrant, croscarmellose sodium, was proven to be chemically morestable with the drug substance than other disintegrants such as sodiumstarch glycolate or polyvinylpyrrolidone. Additionally, the tablet filmcoating system was also designed to minimize oxidative degradationthrough the selection of plasticizer. Triacetin is the plasticizer ofchoice based on chemical stability and was proven to be more stable thanother plasticizers such as polyethylene glycol.

Table 1 below summarizes the stability results by high-pressure liquidchromatography observed for the three different processes.

TABLE I Comparison of Lasofoxifene Stability Conventional Wet Drug InSolution Manufacturing Granulation Wet Granulation Process DryGranulation (comparative) (comparative) Percent Drug Load 0.14 0.28 0.068 Total Percent Initial 0.02 Not Available 0.95 Impurities TotalPercent 0.13 at 12 months 0.54 at 6 weeks 1.43 at 6 weeks Impurities at5° C. Total Percent 0.13 at 12 months 1.21 at 6 weeks 2.03 at 6 weeksImpurities at 30° C. Total Percent 0.41 at 6 months  4.3 at 6 weeks 3.10at 6 weeks Impurities at 40° C./75% RH Total Percent 0.39 at 6 months5.26 at 6 weeks 4.25 at 6 weeks Impurities at 50° C.

Table II below summarizes the stability results of lasofoxifeneformulations with different disintegrants.

TABLE II Comparison of Lasofoxifene Stability Lasofoxifene:Lasofoxifene: Lasofoxifene: Sodium Starch Polyvinyl CroscarmelloseGlycolate Pyrrolidone Binary Mixture Sodium 1:10 Ratio 1:10 Ratio 1:10Ratio Total Percent Not detected at 6 Not detected at 6 Not detected at6 Impurities at 5° C. weeks weeks weeks Total Percent Not detected at 64.75 at 6 weeks 0.72 at 6 weeks Impurities at weeks 40° C./75% RH

Table III below summarizes the stability results of film coatedlasofoxifene tablet formulations.

TABLE III Comparison of Lasofoxifene Film Coated Tablet StabilityPercent Drug Load 1.42 0.34 Film Coat Plasticizer Polyethylene GlycolTriacetin Total Percent Impurities at 0.06 at 12 weeks 0.08 at 6 months5° C. Total Percent Impurities at 0.34 at 12 weeks  0.2 at 6 months 30°C. Total Percent Impurities at 1.74 at 12 weeks  0.2 at 6 months 40°C./75% RH

Immediate release low dosage formulations of the present invention wereprepared as exemplified below.

1. To an appropriate sized high shear blender was added, in order:anhydrous lactose, microcrystalline cellulose, croscarmellose sodium,silicon dioxide and blended for 5 minutes at appropriate impeller andgranulator speeds.

2. Lasofoxifene tartrate was introduced and blended for 15 minutes atappropriate impeller and granulator speeds.

3. Active blend was discharged from the high shear blender.

4. Active blend was charged into an appropriate size twin shell or binblender and blended for 5 minutes.

5. One-half of the magnesium stearate was added to the active blend andblended for 5 minutes.

6. The active blend was compacted on an appropriate roller compactorunit at the appropriate roller pressure, roller speed and feed rate.

7. The active compacts were milled through an appropriate mill fittedwith a 20 mesh (0.033″) screen or equivalent.

8. The milled active blend was charged into an appropriate size twinshell or bin blender and blended for 5 minutes.

9. The second half of the magnesium stearate was added to the milledactive blend and blended for 5 minutes.

10. The final blend was compressed on a rotary tablet press fitted withthe appropriate size tooling at a weight of 100 mg.

11. Tablet cores were film coated in an appropriate size film-coatingunit. The appropriate amount of opacifying and polishing film coats wasapplied to the tablets.

Example No. 1 Lasofoxifene 0.25 mg Film Coated Tablet Composition

Component Grade Mg/Tablet Function Lasofoxifene Tartrate¹ Pfizer 0.341Active Compound Lactose, Anhydrous² NF/USP/Eu/JP 70.159 Diluent/FillerMicrocrystalline Cellulose NF/Eu/JP 25.000 Diluent/Filler CroscarmelloseSodium NF/Eu/JP 3.000 Disintegrant Silicon Dioxide NF/Eu 0.500 GlidantMagnesium Stearate NF/Eu/JP 1.000 Lubricant Opadry II ® (Y-30-13579-A)Pfizer 4.000 Opacifying Coat (Lactose Monohydrate) (NF/Eu/JP) (1.60)(Diluent/Filler) (Hydroxypropyl Methyl (USP/Eu/JP) (1.12) (Polymer)Cellulose 2910-15 cP) (Titanium Dioxide) (USP/Eu/JP) (0.94) (Opacifier)(Triacetin) (USP/Eu/JPE) (0.32) (Plastisizer) (FD&C Yellow No. 6Aluminum (21 CFR, E110) (0.02) (Colorant) Lake 15%-18%) Opadry Clear ®(YS-2-19114-A) Pfizer 0.500 Polish Coat (Hydroxypropyl Methlycellulose(NF/Eu/JP) (0.45) (Polymer) 2910-15 cP) (Triacetin) (USP/Eu/JPE) (0.05)(Plastisizer) Total 104.500 ¹Based on a theoretical potency of 73.4%²Weight adjusted for slight potency changes in the lasofoxifene tartrate

Example No. 2 Lasofoxifene 0.5 mg Film Coated Tablet Composition

Component Grade Mg/Tablet Function Lasofoxifene Tartrate¹ Pfizer 0.681Active Compound Lactose, Anhydrous² NF/USP/Eu/JP 69.819 Diluent/FillerMicrocrystalline Cellulose NF/Eu/JP 25.000 Diluent/Filler CroscarmelloseSodium NF/Eu/JP 3.000 Disintegrant Silicon Dioxide NF/Eu 0.500 GlidantMagnesium Stearate NF/Eu/JP 1.000 Lubricant Opadry II ® (Y-30-13579-A)Pfizer 4.000 Opacifying Coat (Lactose Monohydrate) (NF/Eu/JP) (1.60)(Diluent/Filler) (Hydroxypropyl Methyl (USP/Eu/JP) (1.12) (Polymer)Cellulose 2910-15 cP) (Titanium Dioxide) (USP/Eu/JP) (0.94) (Opacifier)(Triacetin) (USP/Eu/JPE) (0.32) (Plastisizer) (FD&C Yellow No. 6 (21CFR, E110) (0.02) (Colorant) Aluminum Lake 15%-18%) Opadry Clear ®(YS-2- Pfizer 0.500 Polish Coat 19114-A) (Hydroxypropyl (NF/Eu/JP)(0.45) (Polymer) Methlycellulose 2910-15 cP) (Triacetin) (USP/Eu/JPE)(0.05) (Plastisizer) Total 104.500 ¹Based on a theoretical potency of73.4% ²Weight adjusted for slight potency changes in the lasofoxifenetartrateFor comparison to the tablets described in Examples 14-17, Control 1tablets were formed using conventional immediate release dosage formtableting excipients.

The terms and expressions which have been employed in the foregoingspecification are used as terms of description and not of limitation,and there is no intention in the use of such terms and expressions ofexcluding equivalents of the features shown and described or portionsthereof, it being recognized that the scope of the invention is definedand limited only by the claims which follow:

1. A pharmaceutical film coated tablet consisting of a tablet core, anopacifying coat and a polish coat wherein the tablet core comprisesabout 0.3 w/w % to about 14.0 w/w % of(−)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-ylethoxy)phenyl]-5,6,7,8-tetrahydronaphthalen-2-olor a pharmaceutically acceptable salt thereof; about 3.0 w/w % ofcroscarmellose sodium; about 0.5 w/w % of silicon dioxide; about 1.0 w/w% of magnesium stearate and about 81.0 w/w % to about 95.0 w/w % of amixture of lactose and microcrystalline cellulose; the opacifying coatconsists of lactose monohydrate, hydroxypropyl methyl cellulose;titanium dioxide, triacetin and FD&C Yellow No. 6 Aluminum Lake; and thepolish coat consists of hydroxypropyl methylcellulose and triacetin. 2.The pharmaceutical film coated tablet of claim 1, wherein the tabletcore comprises about 0.3 w/w % of(−)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-ylethoxy)phenyl]-5,6,7,8-tetrahydronaphthalen-2-olor a pharmaceutically acceptable salt thereof; and is about 70 w/w % oflactose and about 25 w/w % of microcrystalline cellulose.
 3. Thepharmaceutical film coated tablet of claim 1, wherein the tablet corecomprises about 0.7 w/w % of(−)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-ylethoxy)phenyl]-5,6,7,8-tetrahydronaphthalen-2-olor a pharmaceutically acceptable salt thereof; is about 70 w/w % oflactose and about 25 w/w % of microcrystalline cellulose.
 4. Thepharmaceutical film coated tablet of claim 1, 2 or 3, wherein the(−)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-ylethoxy)phenyl]-5,6,7,8-tetrahydronaphthalen-2-olis in the form of the D-tartrate salt thereof.
 5. A pharmaceutical filmcoated tablet consisting of a tablet core, an opacifying coat and apolish coat wherein the tablet core consists of 0.341 mg of theD-tartrate salt of(−)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-ylethoxy)phenyl]-5,6,7,8-tetrahydronaphthalen-2-ol;70.159 mg anhydrous lactose, 25.000 mg of microcrystalline cellulose,3.000 mg of croscarmellose sodium; 0.500 mg of silicon dioxide; 1.000 mgof magnesium stearate; the opacifying coat consists of 1.60 mg oflactose monohydrate, 1.12 mg of hydroxypropyl methyl cellulose2910-15cP, 0.94 mg of titanium dioxide, 0.32 mg of triacetin and 0.02 mgof FD&C Yellow No. 6 Aluminum Lake 15%-18%; and the polish coat consistsof 0.45 mg of hydroxypropyl methylcellulose 2910-15cP and 0.05 mg oftriacetin.
 6. A pharmaceutical film coated tablet consisting of a tabletcore, an opacifying coat and a polish coat wherein the tablet coreconsists of 0.681 mg of the D-tartrate salt of(−)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-ylethoxy)phenyl]-5,6,7,8-tetrahydronaphthalen-2-ol;69.819 mg anhydrous lactose, 25.000 mg of microcrystalline cellulose,3.000 mg of croscarmellose sodium; 0.500 mg of silicon dioxide; 1.000 mgof magnesium stearate; the opacifying coat consists of 1.60 mg oflactose monohydrate, 1.12 mg of hydroxypropyl methyl cellulose2910-15cP, 0.94 mg of titanium dioxide, 0.32 mg of triacetin and 0.02 mgof FD&C Yellow No. 6 Aluminum Lake 15%-18%; and the polish coat consistsof 0.45 mg of hydroxypropyl methylcellulose 2910-15cP and 0.05 mg oftriacetin.